Sunday, April 29, 2012

Does the FDA discriminate against antidepressants?

The FDA came out with a new warning on citalopram on 3/28/2012. The main point of the warning is that citalopram may lead to electrocardiogram changes that can be associated with an abnormal heart rhythm or arrhythmia that is potentially fatal. The specific change is prolongation of the QTc interval or the interval that correlates with the total duration of ventricular activation and recovery.

Citalopram is a widely used antidepressant medication and it widely used for three reasons. It is not likely to have a lot of interactions with other drugs. Citalopram figured prominently in the STAR*D algorithm from the largest study done on enhancing antidepressant effectiveness. A third reason is that it is a generic medication and it is very inexpensive. Psychiatrists have broad experience with the drug and the general experience is that it is well tolerated with little toxicity.

Flecainide is a Type IC antiarrhythmic agent indicated for the prevention of paroxysmal atrial fibrillation (AF), paroxysmal supraventricular tachycardia (PSVT), and the prevention of life-threatening ventricular arrhythmias like sustained ventricular tachycardia. The FDA warnings on the drug include proarrhytmic effects and excess mortality. The excess mortality was directly observed in a clinical trial done to suppress ventricular arrhythmias.

The black box warnings for each drug listed below are directly from Medline:

Looking at the safety concerns for both medications - important differences emerge. First, the FDA recommends maximum doses for the citalopram not just for the a maximum dose for adults but in specific conditions including aging. Searching the FDA web site shows exactly 25 references for safety concerns of flecainide and none of them contain that level of information. Second, the citalopram warning shows a table of QTc interval changes by dose for both citalopram and escitalopram. There is no information in FDA documents (that I could find) for flecainide even though it is widely accepted that flecainide causes dose related changes in not just the QTc interval but also the QRS and PR intervals along with a host of additional effects on cardiac pacemakers and conduction. The overall tone of the release is that citalopram is a potentially cardiotoxic drug. Third, the ECG monitoring recommendations are not internally consistent. The absolute cut off of a QTc interval of 500 ms is highly unlikely - even in cases where the patient is taking 60 mg per day or more of citalopram. It is also unlikely that the QTc intervals in the citalopram warning will lead to a QTc interval of greater than 500 ms. This will result in tens of thousands of ECGs done because that is the only way that the QTc interval can be determined.

The black box warnings and the recently issued warning all considered, serious questions are raised relative to drugs with known cardiotoxicity and the whole issue of QTc warnings in all psychiatric drugs. Certainly nobody wants a rare severe complication as a result of a prescription medication but can it really be avoided? What good would ECG screening do? There have not been any trials to address that issue of whether all patients taking citalopram need baseline ECGs. All the patients taking flecainide have probably had multiple ECGs done that indicate a possible need for treatment but there is little guidance on the ECG issue. In many patients taking flecainide, patients get serial ECGs and they do exercise stress tests to rule out proarrhythmic effects. Are the same precautions needed for patients on citalopram?

Are the thresholds for treatment different given the fact that flecainide caused increased mortality during clinical trials and citalopram did not? There would be an argument that flecainide is used to treat life-threatening arrhythmias, but the other indication is for prevention of atrial fibrillation and atrial fibrillation is not a life threatening arrhythmia. With regard to the seriousness of the diagnosis, major depression carries a lifetime mortality of 10%. Finally, where is the table on the relationship between flecainide dose and QTc prolongation like we see for both citalopram and escitalopram? Is it possible that flecainide has more of an effect throughout the dosage range than citalopram?

These are serious questions given that I have already established that there is a significant bias in the media against psychiatry, psychiatrists and psychiatric medications. The most recent FDA warning has created a lot of anxiety for psychiatrists and any patient taking citalopram. The majority of those patients are being seen by primary care physicians.

If citalopram is that cardiotoxic, let's see the evidence and let's see how it compares to a medication with known cardiotoxicity. Let's have the same level of warning for both medications and some concrete ideas about what needs to be done to manage that risk.

5 comments:

Could these factors be part of the reasons for the 35 year lower life expectancy in those with chronic mental illness? The more meds that prolong the QT interval, the greater the risks. Older meds carry a great risk of this as well-such as Trazdeone and trycyclics.

The bias against psychiatry is likely the lack of needed research to discover new meds that are safe., Another bias is not engaging in appropriate testing of folks who take these meds to discover who is at risk. Most would be fine but the ones who have the cardiac impact are at greater risk of sudden death. Regular Ekg's would allow for discovery of those at risk so adjustments to medication can be made-adding a beta blocker or considering an AICD in extreme cases and severe psychiatric illness.

Newcomer and Hennekens do an excellent job of looking at the problems and potential solutions: http://jama.jamanetwork.com/article.aspx?articleid=209157

Many of the patients taking citalopram are otherwise healthy and do not have the risk factors that they discuss in their article.

One of the key questions that I highlight in this post is the fact that many nonpsychiatric drugs carry a higher risk that is not borne out by the potential lethality of the underlying condition. I don't think that anyone would question my example of flecainide in this example being much more potent than citalopram in terms of conduction effects. It was after all associated with excessive mortality in the clinical trials. Where is the actual data in the case of citalopram? Further - what are the recommended monitoring measures to use this drug safely?

ICDs or implantable defibrillators save lives but are expensive therapy. They are sometimes challenged for cost effectiveness, but studies support that ICD therapy is indeed cost effective. The biggest challenge is getting people who could benefit from ICDs to realize they might need one. Three out of four people who could get life-saving benefits from an ICD do not have one!

I'm on this SSRI and have recently gone into Afib. After reading some reports on this connection I'm attempting to reduce my dose (slowly) and hopefully switch to an alternative. I've been put on flecinide since the afib started, it would seem to mixing these two together would increase the risks greatly.

Determining the risk of medications can't really be done by reading side effect literature. It needs to be done by the physicians who know you and who are prescribing these medications. The intent of this post is just a side by side comparison of how the FDA handles two very different medications based on their own FDA approved side effect literature. Since this post I have come to realize that FDA decisions have a political bias and that as a regulatory agency scientific comparisons are not the highest priority.